This project will determine the mechanisms by which environmental tobacco smoke (ETS) modify defined phases of the human allergic response in children. Epidemiological data suggests that parental smoking is a major risk factor for allergic sensitization. We will determine the in vivo biological effects of ETS on the induction and enhancement of the specific allergic airway response under clinically relevant conditions and dissect the cellular and molecular mechanisms involved. We will use inhalation challenges in adults and children to define directly how ETS exposure either induces d novo and/or exacerbates ongoing allergic inflammation in the human airway. These human studies will be complemented with animal studies which will answer key genetic and developmental issues that can not be addressed as rigorously in humans. Aim #1 will determine the mechanisms by which ETS alters the in vivo IgE antibody response in the human upper airway. We will determine if ETS directly alters IgE production from mucosal B cells (by inducing germ line transcription or isotype switching) or if it acts indirectly by modifying the airway mucosal environment (by inducing cytokine production or cell surface receptors). Aim #2 will determine if exposure to ETS alters IgE- independent inflammatory responses in the human upper airway by increasing chemokine production (MCP-1, MCP-3, MIP-1alpha, RANTES and eotaxin) or their ability of increasing cellular infiltration and activation. Both of these aims will rely on ETS inhalation challenge studies on groups of allergic non-asthmatic children and adults. Aim #3 will test the hypothesis that the in vivo allergic antibody response due to chronic exposure to ETS is controlled by genetic background and age by using an established animal model. Our studies integrate with Dr. Gong since we will collaborate in the actual ETS inhalation challenges using his exposure chamber at his site. Our work will provide new insights into environmental effects of childhood allergic disease by performing direct experimentation to answer questions previously studied by solely epidemiologic means.